New treatment options for patients with metastatic prostate cancer.

Prostate cancer is one of the most common cancers in men. When metastasised (40% of patients), classic anti-androgen therapy is the first-line treatment. Usually, this treatment becomes ineffective when castration-resistant prostate cancer (CRPC) develops. Thus far, docetaxel was the only chemotherapeutic option that has shown to be able to extend overall survival and improve quality of life in these patients. Recently, cabazitaxel and abiraterone have shown significant survival benefits for patients progressive on or after docetaxel treatment, as did enzalutamide and radium-223. In North America, immune therapy (sipuleucel-T) became available for a subgroup of CRPC patients. These new treatment options will change the treatment paradigm of patients with metastatic castration resistant prostate cancer. A multidisciplinary approach by both medical oncologists and urologists seems mandatory.

Absence of severe systemic toxicity after leakage-controlled isolated limb perfusion with tumor necrosis factor-alpha and melphalan.

BACKGROUND: Severe systemic toxicity and hemodynamic changes after isolated limb perfusion (ILP) with tumor necrosis factor-alpha (TNF-alpha) and melphalan, with or without interferon-gamma, have been reported in several series. We studied whether these side effects could be precluded by preventing leakage from the isolated circuit into the systemic circulation. METHODS: Clinical and pharmacokinetic data for 20 consecutive patients with recurrent melanoma of the limbs who were treated by ILP with TNF-alpha (3-4 mg) and melphalan, with or without interferon-gamma, were studied. Leakage rates and TNF-alpha levels were determined during and after ILP and were correlated with systemic toxicity and hemodynamic changes. RESULTS: Only two patients experienced leaks (2% and 13%) during ILP. For 18 patients without leakage, the mean peak systemic TNF-alpha level was 2.8 ng/ml at 10 minutes after ILP. After leakage, the peak systemic TNF-alpha levels were 31.9 and 88.3 ng/ml at 5 minutes. Toxicity was mild and consisted mainly of fever (n = 17) and nausea/vomiting (n = 19) during the first day after ILP. Some patients developed tachycardia (n = 6), hypotension (n = 3; responding immediately to fluid challenge), a decrease in the WBC count (n = 3; grade I) or thrombocyte count (n = 11; grade I/II, no hemorrhage or therapeutic intervention), or hepatotoxicity [cytolysis (n = 15; 14 grade I/II and 1 grade IV) or hyperbilirubinemia (n = 7; grade I/II, all resolving spontaneously)]. Patients with tachycardia or hepatotoxicity exhibited significantly higher TNF-alpha levels after ILP, compared with other patients. CONCLUSIONS: Systemic toxicity after ILP with TNF-alpha is minimal and does not differ from that after ILP with melphalan alone when leakage is adequately controlled.

IL-1 beta does not cause neutrophil degranulation but does lead to IL-6, IL-8, and nitrite/nitrate release when used in patients with cancer.

The use of IL-1 in humans is associated with dose-limiting toxicity which resembles that of TNF-alpha or IL-2. Activation of neutrophils is thought to contribute to the toxicity caused by these two cytokines. We studied the effect of IL-1 in vivo on changes in neutrophil numbers and neutrophil degranulation as well as on the formation of neutrophil agonists, such as complement activation products, and on levels of TNF, IL-6, IL-8, and nitrite/nitrate (as a measure of nitric oxide production). Six patients with metastatic melanoma were treated with 3 ng/kg recombinant human IL-1 beta daily. One hour after the start of the 30-min IL-1 infusion, which caused mild cardiovascular toxicity, plasma levels of IL-6 reached a peak of 25 +/- 9 ng/L (mean +/- SEM), IL-8 reached a peak of 311 +/- 100 ng/L at 2 h, and nitrite/nitrate peaked after 10 h to 89 +/- 27 mumol/L. IL-1 did not induce significant changes in plasma levels of TNF or of the complement activation products C3a and C4b/c. Although IL-1 induced neutrophilia, levels of elastase and lactoferrin did not change. The failure of IL-1 to degranulate neutrophils was confirmed in an ex vivo model with whole blood culture in which doses of up to 100 microgram/L IL-1 beta or IL-1 alpha failed to induce significant elastase or lactoferrin release, whereas TNF, tested as a positive control, was able to do so. These results demonstrate that, unlike TNF, IL-1 does not cause neutrophil degranulation in man, despite its ability to cause neutrophilia and the rapid release of IL-6, IL-8, and nitrite/nitrate.

A pilot study to evaluate the effects of C1 esterase inhibitor on the toxicity of high-dose interleukin 2.

In a pilot study six patients received 4 days' treatment with interleukin 2 (IL-2) [cumulative dose (CD) 264 +/- 26 x 10(6) IU m-2] and C1 esterase inhibitor (C1-INH) (loading dose 2,000 U, followed by 500-1,000 U twice daily). Toxicity was compared with that in patients given 4 days' treatment with standard (CD 66 +/- 12 x 10(6) IU m-2) or escalating-dose (CD 99 +/- 8 x 10(6) IU m-2) IL-2. IL-2-induced hypotension was equivalent and complement activation was less after IL-2 + C1-INH (C3a = 10.5 +/- 3.2 nmol l-1) than following standard (14.1 +/- 8.4 nmol l-1) or escalating-dose (18.3 +/- 2.9 nmol l-1) IL-2. This study demonstrates that C1-INH administration during IL-2 treatment is safe and warrants further study to evaluate its ability to ameliorate IL-2-induced toxicity.

Initial studies on the administration of C1-esterase inhibitor to patients with septic shock or with a vascular leak syndrome induced by interleukin-2 therapy.

Activation of the complement and contact systems occur in patients with septic shock and is associated with a poor outcome. Activation of both systems is regulated by a common inhibitor, C1-esterase inhibitor (C1-Inh). Functional levels of C1-Inh are normal or slightly decreased in septic patients although this inhibitor is an acute phase protein. Moreover, an increased turn-over of C1-Inh in sepsis likely occurs since levels of proteolytically inactivated ("modified") C1-Inh are increased in this syndrome. One may therefore postulate that in sepsis there is a relative deficiency of C1-Inh. Here we will summarize our preliminary studies in 11 patients with septic shock, who received high doses of C1-Inh for up to 5 days. Activation of complement and contact systems also occurs in "a human model for septic shock" i.e., the vascular leak syndrome (VLS) induced by immunotherapy with the cytokine interleukin-2 (IL-2). The similarity between VLS and sepsis is not only reflected by similar patterns of complement and contact activation, but also by comparable hemodynamic and biochemical changes, and by the involvement of a number of other inflammatory mediators, such as the release of pro-inflammatory cytokines, and activation of coagulation and fibrinolysis and of neutrophils. Here we will also summarize our initial studies of the effect of C1-Inh administration to 6 patients with the VLS induced by IL-2. Our results indicate that high doses of C1-Inh can be safely administered to patients with septic shock or with the VLS, and may attenuate complement and contact activation in these conditions. Whether this therapy may reduce mortality and or morbidity of either syndrome has to be established by double-blind controlled studies.

C1-inhibitor substitution therapy in septic shock and in the vascular leak syndrome induced by high doses of interleukin-2.

C1-inhibitor (C1-INH) is the major plasma inhibitor of the complement and contact systems. Activation of either system has been shown to occur in patients with septic shock and is associated with a poor outcome. Functional levels of C1-INH tend to be normal in septic patients although paradoxically this inhibitor is an acute phase protein. Moreover, levels of proteolytically inactivated C1-INH are increased in sepsis pointing to an increased turn-over. These observations suggest a relative deficiency of biologically active C1-INH in sepsis. Complement and contact activation have also been shown to occur in the vascular leak syndrome (VLS) induced by immunotherapy with the cytokine interleukin-2 (IL-2), which syndrome may be regarded as a human model for septic shock. The similarity between VLS and sepsis encompasses more than complement and contact activation since a number of other inflammatory mediators considered to play a role in the pathogenesis of septic shock, are also involved in the development of VLS. The role and the mechanisms of complement and contact activation in sepsis and in the VLS are reviewed in this paper. Initial results of intervention therapy with high doses of C1-INH in these syndromes are also reported. It is concluded that high doses of C1-INH can be safely administered to patients with septic shock or with the VLS and may attenuate complement and contact activation in these conditions. Double-blind controlled studies are needed to definitely proved these effects and to establish whether this treatment is able to reduce mortality and morbidity of these syndromes.

Plasma lipid peroxides and antioxidants in human septic shock.

In order to assess if an oxidant/antioxidant imbalance is involved in human septic shock and its outcome, we measured plasma levels of the lipid peroxides malondialdehyde--as thiobarbituric acid reactive substance--conjugated dienes and fluorescent products, together with the antioxidants alpha-tocopherol, glutathione peroxidase activity and selenium in 12 patients with septic shock and compared them with values of normal controls. At first measurements, malondialdehyde (median 3.9 mumol/l; range 2-38.8) and fluorescent products (median 21.2%; range 9.4-134) were elevated (p less than 0.05), alpha-tocopherol (median 15 mumol/l; range 7-25) and selenium (median 0.76 micrograms/ml; range 0.49-1.09) were depressed (p less than 0.05). Conjugated dienes and glutathione peroxidase activity were in the normal range. In non-survivors (n = 5) initial levels of malondialdehyde and fluorescent products (median 11 versus 3.1 mumol/l; 74 versus 13% respectively) were higher than in survivors (p less than 0.05) and initial selenium levels were lower (median 0.58 versus 0.92 micrograms/l; p less than 0.05). These results are consistent with the concept that an oxidant/antioxidant imbalance--as indicated by elevated plasma lipid peroxides and depressed antioxidants--is involved in human septic shock and a fatal outcome.

Twenty-four-hour ambulatory oesophageal pH monitoring: experience in The Netherlands.

Twenty-four-hour ambulatory oesophageal pH monitoring has become a major diagnostic method for the evaluation of gastro-oesophageal reflux disease. Essential requirements for registration and reproduction of the pH are reliable pH electrodes, well-performed calibration and optimal reproduction and analysis of the signal. The most commonly used pH probes in The Netherlands are not-combined monocrystalline antimony electrodes (Synectics Ltd, Sweden) and combined glass electrodes (Ingold and Radiometer). For diagnostic intra-oesophageal pH measurements both types are suitable; for research purposes, especially intragastric, glass electrodes are preferable. In The Netherlands several types of solid-state recorders are commercially available: all fulfill the conditions necessary to produce reliable registrations. In the present study, available measuring systems in The Netherlands and current practices associated with ambulatory pH monitoring were evaluated. Inquiry among the Dutch pH registration centres showed that more than half were using Synectics electrodes and equipment. Positioning of the pH probe was based on manometry (25%), fluoroscopy (22%) or endoscopy (20%). In the initial phase there were many problems, especially related to ignorance of the complicated registration procedure. For ambulatory pH measurements we recommend a simple datalogger with a sufficient memory capacity and direct interface with a PC, a combined glass electrode positioned 5 cm above the manometrically determined lower oesophageal sphincter. For clinical interpretation of the results the percentage of time with pH below 4 is probably the most reliable parameter for the detection of pathological gastrooesophageal reflux.